DESCRIPTION: (Applicant's Abstract) This is a new application submitted in response to NIDA RFA DA-96-003, "Novel Pharmacotherapies for Cocaine and Other Psychostimulant Dependence." A new clinical laboratory model of relapse prevention is proposed to evaluate novel approaches to the treatment of cocaine abuse, amphetamine abuse and polydrug abuse involving cocaine and alcohol (cocaethylene). Men and women who meet DSM-IV criteria for stimulant abuse will be studied to determine if there are gender differences in response to treatment. Women will be studied at two phases of the menstrual cycle (the mid-follicular and mid-luteal phase). Studies will be conducted on a residential clinical research unit, and each subject will serve as his/her own control under double-blind placebo-treatment and active treatment conditions. AIDS risk reduction counseling will be provided. The effects of novel treatments on the subjective, discriminative, physiologic and reinforcing effects of the target psychostimulant will be studied under two conditions. First, the effects of the treatment drug (or its placebo) on the subject's ability to detect and discriminate the active psychostimulant from a placebo-stimulant will be examined with subjective, physiologic and behavioral measures. Then the subject will be allowed to work at a simple operant task to self-administer repeated doses of the same psychostimulant over six hours. We hypothesize that treatments that reduce the subjective, discriminative and physiologic effects of psychostimulants will also reduce relapse to drug seeking as measured objectively with drug self-administration procedures and self-reports of drug craving. We propose two novel therapeutic approaches using clinically available medications that have not previously been used to treat psychostimulant abuse. However, preclinical findings suggest that each approach may be effective in reducing the biologic and behavioral effects of psychostimulants. One approach involves stimulation of a naturally occurring glycoprotein that reduces cocaine levels in blood. This glycoprotein in blood has a molecular structure similar to the dopamine transporter. A second approach involves treatment with a model of kappa opioid agonist activity. Kappa agonists reduce cocaine's behavioral, discriminative and reinforcing effects in preclinical studies. These novel treatment approaches may lead to new directions for medications development and more effective treatment of psychostimulant and polydrug abuse.